Genetic and functional studies of a missense variant in a glutamate transporter, SLC1A3, in Tourette syndrome

Adamczyk, Abby; Gause, Colin D.; Sattler, Rita; Vidensky, Svetlana; Rothstein, Jeffery D.; Singer, Harvey S.; Wang, Tao

doi:10.1097/ypg.0b013e328341a307

Cited by 55 publications

(35 citation statements)

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“…Therapeutically, tic suppression did not differ from a placebo control group following treatment with either a glutamate agonist (D-serine) or a glutamate antagonist (riluzole) 22 . A missense mutation in the glutamate transporter gene (SLC1A3) has been identified in a small number of GTS patients 15,23 .…”

Section: Glutamatementioning

confidence: 99%

Gilles de la Tourette syndrome

Robertson

Eapen

Singer

et al. 2017

Nat Rev Dis Primers

285

244

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The unstructured abstract of 200 words maximum should summarize the main points of the article. All information mentioned in the abstract must be addressed somewhere in the main article. The abstract should not contain references or display item citations. Gilles de la Tourette Syndrome (GTS), a reasonably common disorder, has had a long, tortuous and somewhat controversial history. First and well described in the 18th century 1,2 , the main features of GTS have, however, remained fairly constant. The core diagnostic features are multiple motor and one or more vocal (phonic) tics lasting for over a year. In addition, almost pathognomic, but not necessary, features described in the early documentations include coprolalia (involuntary, inappropriate swearing), and echophenomena (copying behaviours), as well as many co-morbidities and psychopathologies 3 . Introduction [suggested 500 words, is 544 words -8 refs] Mary Robertson Thoughts for Mary -Your word count when combining sections 1 and 2 is 1001 (1000 limit)-so OKGTS was originally described in France and the majority of early literature came from and standardised schedules such as diagnostic confidence, measurement of severity, QoL, and assessment of both co-morbidities and co-existent psychopathologies are currently available.Large international collaborative consortia are engaged in studies exploring aetiological factors in particular, and some international treatment studies are also underway. Perhaps as a result of earlier small patient numbers, the treatment trials have given good clues to management, but unsurprisingly systematic reviews and meta-analyses have been hampered, giving disappointing, if not unexpected, results. Intriguingly medications from the typical NRDP -Gilles de la Tourette Syndrome 3 antipsychotic family including haloperidol, which first had documented success in 1961 6,7 are still being used, although successive generations of "atypicals" are currently more in vogue,as are medications such as alpha-2-adrenergic agonists. Interestingly, haloperidol remains the only medication prescribed on licence in many parts of the world. In contrast to disorders such as ADHD, in which it is clear which treatments work and which do not require further study 8 , a variety of treatment studies in GTS are still being undertaken, including using other medications (trying to improve efficacy and reduce side effects), behavioural therapies, deep brain stimulation (for refractory cases), and other more "alternative" methods such as "orthotics" (teeth braces). The GTS community has to first agree on how common GTS is and then seek funding for research in the areas of major importance.2. Epidemiology [suggested 500 words, is 444 words, 6 additional refs] Mary Robertson GTS was for many years thought to be not only very rare, but a bizarre curiosity, with sporadic case reports peppering the literature. The belief that GTS was uncommon at the very least was held by many until Comings 9 controversially suggested that GTS occurred in between 0.66% and...

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Section: Glutamatementioning

confidence: 99%

Gilles de la Tourette syndrome

Robertson

Eapen

Singer

et al. 2017

Nat Rev Dis Primers

285

244

View full text Add to dashboard Cite

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“…Glutamate has an essential role in pathways involved with CSTC circuits and an extensive interaction with dopaminergic systems . Several lines of evidence support a possible role of the glutamatergic system in TS including results of familial genetic studies (Barr et al, 1999; Tourette Syndrome Association International Consortium for Genetics, 2007;Adamczyk et al, 2010) and reduced levels of glutamate in globus pallidus interna, globus pallidus externa, and substantia nigra pars reticulata in a small number of postmortem brains (Anderson et al, 1992). Altered cholinergic neurotransmission has been implicated by the postmortem finding of decreased numbers of cholinergic interneurons in the striatum of TS patients (Kataoka et al, 2010).…”

Section: Neurotransmitter Studiesmentioning

confidence: 99%

Neurobiology of Tourette Syndrome: Current Status and Need for Further Investigation: Table 1.

Felling¹,

Singer²

2011

J. Neurosci.

199

116

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Tourette syndrome (TS) is a common, chronic neuropsychiatric disorder characterized by the presence of fluctuating motor and phonic tics. The typical age of onset is ϳ5-7 years, and the majority of children improve by their late teens or early adulthood. Affected individuals are at increased risk for the development of various comorbid conditions, such as obsessive-compulsive disorder, attention deficit hyperactivity disorder, school problems, depression, and anxiety. There is no cure for tics, and symptomatic therapy includes behavioral and pharmacological approaches. Evidence supports TS being an inherited disorder; however, the precise genetic abnormality remains unknown. Pathologic involvement of cortico-striatal-thalamo-cortical (CSTC) pathways is supported by neurophysiological, brain imaging, and postmortem studies, but results are often confounded by small numbers, age differences, severity of symptoms, comorbidity, use of pharmacotherapy, and other factors. The primary site of abnormality remains controversial. Although numerous neurotransmitters participate in the transmission of messages through CSTC circuits, a dopaminergic dysfunction is considered a leading candidate. Several animal models have been used to study behaviors similar to tics as well as to pursue potential pathophysiological deficits. TS is a complex disorder with features overlapping a variety of scientific fields. Despite description of this syndrome in the late 19th century, there remain numerous unanswered neurobiological questions.In the 1880's, Georges Gilles de la Tourette published a two-part article in which he emphasized differences between tics and chorea. Although many of the descriptions about the disorder, which now bears his name [Tourette syndrome (TS)], have been revised, his belief that tics are a neurological movement disorder and not a psychiatric condition persists to the present (Goetz and Klawans, 1982). Nevertheless, despite multiple advances and widespread acceptance of TS being a biological disorder, the precise etiology and underlying pathophysiological mechanisms remain unknown. The goals of the present review are to briefly describe the clinical phenomenology of TS and related tic disorders, to review current information on genetic and neurobiological mechanisms, and to identify areas in need of further investigation.

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“…Such perturbations in the balance between excitatory glutamatergic and inhibitory GABAergic transmission within regulatory corticostriato-thalamocortical circuits have long been hypothesized as a core defect in Tourette syndrome pathogenesis. [15][16][17] Taken together, our findings highlight an often underestimated function of astrocytes in supporting synaptic function and suggest that abnormalities in this process may contribute to the etiology of Tourette syndrome. Gene P-values are not corrected for multiple testing.…”

Section: Discussionmentioning

confidence: 55%

“…This is the first study to point to the involvement of ANMC function in Tourette syndrome, probably through altered glycogen and glutamate/GABA metabolism, and in line with previously hypothesized mechanisms underlying Tourette syndrome pathogenesis that involve perturbations in the balance between excitatory glutamatergic and inhibitory GABAergic transmission within regulatory cortico-striato-thalamocortical circuits. [15][16][17] The ANMC gene set contains astrocyte-enriched genes involved in various energy metabolism processes that support synaptic function 18 ( Figure 1). First, whereas neurons have a low glycolytic rate, astrocytes actively take up glucose from the circulation, store it as glycogen and subsequently convert glycogen to lactate for release into neurons under neuronal command.…”

Section: Discussionmentioning

confidence: 99%

Involvement of astrocyte metabolic coupling in Tourette syndrome pathogenesis

et al. 2015

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Tourette syndrome is a heritable neurodevelopmental disorder whose pathophysiology remains unknown. Recent genome-wide association studies suggest that it is a polygenic disorder influenced by many genes of small effect. We tested whether these genes cluster in cellular function by applying gene-set analysis using expert curated sets of brain-expressed genes in the current largest available Tourette syndrome genome-wide association data set, involving 1285 cases and 4964 controls. The gene sets included specific synaptic, astrocytic, oligodendrocyte and microglial functions. We report association of Tourette syndrome with a set of genes involved in astrocyte function, specifically in astrocyte carbohydrate metabolism. This association is driven primarily by a subset of 33 genes involved in glycolysis and glutamate metabolism through which astrocytes support synaptic function. Our results indicate for the first time that the process of astrocyte-neuron metabolic coupling may be an important contributor to Tourette syndrome pathogenesis. INTRODUCTIONTourette syndrome is a childhood-onset neuropsychiatric disorder characterized by chronic, repetitive involuntary movements and vocalizations, that is, motor and vocal tics. Although genetic factors play an important role in the etiology of Tourette syndrome, and results from twin and family studies have indicated strong familiality, 1 the underlying pathophysiology is still unclear. 2 Identifying genetic factors and associated biological mechanisms would be a major step forward, and could provide putative hallmarks for treatment.To date, only one Tourette syndrome genome-wide association study (GWAS) has been published. 3 Their top signal was in the COL27A1 gene with P = 1.85 × 10 − 6 , and there were no genetic variants that reached genome-wide significance. In addition, candidate genes from earlier, smaller-scaled candidate gene studies were not replicated, suggesting that these genes are either not causally related to Tourette syndrome or are only important in specific subtypes of Tourette syndrome. A recent study demonstrated that Tourette syndrome is polygenic and likely influenced by hundreds, possibly thousands, of genetic variants with small effects, and that 475% of Tourette syndrome heritability is captured by common genetic variants included in GWAS chips. 4 An important question that arises from this polygenic nature is whether these thousands of genes of small effect cluster across cellular function or whether they are

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Genetic and functional studies of a missense variant in a glutamate transporter, SLC1A3, in Tourette syndrome

Abstract: These results indicate that E219D is a functional SLC1A3 variant that is presented in a small number of individuals with Tourette syndrome. Further studies on possible changes in glutamate transport in the pathogenesis of Tourette syndrome are warranted.

Cited by 55 publications

References 0 publications

Gilles de la Tourette syndrome

Gilles de la Tourette syndrome

Neurobiology of Tourette Syndrome: Current Status and Need for Further Investigation: Table 1.

Involvement of astrocyte metabolic coupling in Tourette syndrome pathogenesis

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